Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells.
Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells.
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DOI：
10.1158/1541-7786.mcr-15-0089
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Eischen CM
中科院分区：
文献类型：
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作者：
Carrillo AM;Hicks M;Khabele D;Eischen CM
Mdm2 癌基因是 p53 肿瘤抑制因子的负调节因子，也是最近发现的 DNA 断裂修复抑制剂。 Nutlin-3 是 Mdm2/p53 相互作用的小分子抑制剂，可通过激活 p53 诱导癌细胞凋亡。虽然这对于那些带有野生型 p53 的癌症来说是一种很有前景的疗法，但一半的人类癌症已经使 p53 失活。在这里，我们揭示了 Nutlin 的一个先前未被认识到的作用是抑制 DNA 断裂修复，源于其增加 Mdm2 蛋白水平的能力。 Nutlin 诱导的 Mdm2 增加抑制 DNA 双链断裂 (DSB) 修复并延长不依赖于 p53 的 DNA 损伤反应信号传导。从机制上讲，Nutlin 的这种作用需要 Mdm2 并通过 Mre11/Rad50/Nbs1 DNA 修复复合物的 Nbs1 发挥作用。在超过 90% 的 p53 失活的卵巢癌细胞中，Nutlin 与基因毒性药物顺铂或依托泊苷结合，具有协同致死作用，导致 DNA 损伤和细胞凋亡增加。因此，这些数据证明了药理上增加 Mdm2 水平的意外后果，当与基因毒性剂联合使用时，会诱导卵巢癌细胞和可能的其他恶性细胞类型的合成致死，这些细胞已经灭活了 p53。数据揭示了药理学上增加 Mdm2 水平与化疗药物相结合对于失去功能性 p53 的恶性肿瘤具有治疗有益效果。
The Mdm2 oncogene is a negative regulator of the p53 tumor suppressor and recently identified inhibitor of DNA break repair. Nutlin-3 is a small molecule inhibitor of Mdm2/p53 interaction that can induce apoptosis in cancer cells through activation of p53. While this is promising therapy for those cancers with wild-type p53, half of all human cancers have inactivated p53. Here, we reveal a previously unappreciated effect of Nutlin is inhibition of DNA break repair, stemming from its ability to increase Mdm2 protein levels. The Nutlin-induced increase in Mdm2 inhibited DNA double-strand break (DSB) repair and prolonged DNA damage response signaling independent of p53. Mechanistically, this effect of Nutlin required Mdm2 and acted through Nbs1 of the Mre11/Rad50/Nbs1 DNA repair complex. In ovarian cancer cells where >90% have inactivated p53, Nutlin combined with the genotoxic agents, cisplatin or etoposide, had a cooperative lethal effect resulting in increased DNA damage and apoptosis. Therefore, these data demonstrate an unexpected consequence of pharmacologically increasing Mdm2 levels that when utilized in combination with genotoxic agents induces synthetic lethality in ovarian cancer cells, and likely other malignant cell types, that have inactivated p53. Data reveal a therapeutically beneficial effect of pharmacologically increasing Mdm2 levels combined with chemotherapeutic agents for malignancies that have lost functional p53.